Atractylodin alleviates polycystic ovary syndrome by inhibiting granule cells ferroptosis through pyruvate dehydrogenase kinase 4-mediated JAK-STAT3 pathway.

BACKGROUND

Polycystic ovary syndrome (PCOS) is a common endocrine disorder, and its close relationship with oxidative stress has been well-documented. Atractylodin (ATR) plays a role in the treatment of many diseases through its antioxidant function. However, its function in PCOS remains unexplored. In this study, the function and underlying mechanisms of ATR in mitigating PCOS symptoms were investigated.

METHODS

A mouse model of PCOS induced using DHEA and a high-fat diet was established, and many factors such as hormone levels (FSH, LH, testosterone, and progesterone), the estrous cycle, and ovarian shape were evaluated. In vitro, PCOS model was established by DHEA-induced KGN cell, and the effects of ATR on ferroptosis and oxidative stress markers were explored. Specifically, the viability of KGN cells treated with ATR was assessed using the CCK-8 assay, and the levels of malondialdehyde (MDA), glutathione (GSH), and reactive oxygen species (ROS) were measured to evaluate oxidative stress. Expression of ferroptosis-related genes (NRF2, GPX4, SLC7A11) and PDK4 was analyzed by qRT-PCR and Western blotting. PDK4's interaction with ATR was examined through molecular docking and confirmed by surface plasmon resonance (SPR) analysis.

RESULTS

Our data show that the treatment of ATR markedly increased hormone levels and improved normal estrous cycles. Moreover, ATR was found to improve ovarian morphology by decreasing cystic dilatation and increasing the number of corpora lutea. Mechanistically, our research found that ATR regulates the expression of PDK4 by binding to its GLY331 and inhibits granulosa cell ferroptosis by regulating the JAK-STAT3 pathway mediated by PDK4.

CONCLUSIONS

In conclusion, our study suggest that ATR may be a therapeutic option for managing PCOS and PDK4 could be a target for the development of new drugs for PCOS.